Although chronic transfusion is increasingly used to prevent life-threatening events in patients with sickle cell disease (SCD), alloimmunization to blood group antigens remains a major complication of chronic transfusions. We believe that a major contributing factor responsible for RBC alloimmunization is the variation in blood groups of these patients, especially in the Rh system, compared to the predominantly Caucasian donor pool. The main objective of this time-sensitive ancillary study to the Comprehensive Sickle Cell Center collaborative trials is to eliminate transfusion-induced alloimmunization in SCD patients by capitalizing on a nationally representative population of SCD patients as blood samples and relevant clinical data are collected. As a part of the study, we will use RBCs, collected prospectively for the trial and which otherwise would be discarded. Specifically, we aim to (1) determine whether the diversity and frequency of alleles encoding Rh blood group antigens are comparable in SCD patients and African-American blood donors. Using blood and DNA samples from these two populations, we will first determine the molecular bases for complex Rh phenotypes by sequencing the RHD and RHCE genes in those individuals whose serum contains unusual anti- Rh antibodies. The population frequency of these alleles will then be estimated by genotyping samples from SCD patients with simple or no Rh antibodies and from unrelated African American donors residing in the same geographic locations as the patients. (2) Using the knowledge gained from our RH gene sequencing studies together with our experience in designing blood group DNA chips, we will develop comprehensive microchips to detect clinically-relevant alleles in the Rh and other blood group systems. These high-throughput microchips will be designed to screen for donors with clinically significant variant Rh phenotypes and with different combinations of minor antigens, so that antigen-negative inventories may be increased and matching to patients with SCD optimized. (3) Two separate microchip platforms will be tested and compared using DNA samples from the SCD patient and blood donor samples in Aim 1, and an additional 2000 African-American donor samples from the New York Blood Center. Expertise in bioinformatics and specialized tools, including the Blood Operations Support Software developed at the New York Blood Center will permit seamless interfacing of data from multiple sources, as well as analysis and interpretation of the complex genotypic and phenotypic data collected for this project. Taken together, these investigations will enable us to effectively prevent alloimmunization by providing more precisely matched blood to patients with SCD and by allowing for more widespread use of transfusion, have an immediate impact on the care of this patient population. Although chronic transfusion is increasingly used to prevent life-threatening events in patients with sickle cell disease (SCD), alloimmunization to blood group antigens remains a major complication of chronic transfusions. The proposed study is to develop tools to revolutionize the way we type for blood groups antigens to increase inventories of antigen-negative blood and to match blood based on DNA analysis in order to eliminate transfusion-induced alloimmunization. We believe that data generated from this project will have an immediate impact in improving the transfusion of patients with SCD. (End of Abstract)